Lowe syndrome

Disease Description (Causes and Symptoms)

• Cause
  • This is an X-linked recessive genetic disorder caused by a pathogenic change in the OCRL gene (exonucleotide location: Xq26.1). The OCRL gene encodes phosphatidylinositol 4,5-bisphosphate 5-phosphatase (OCRL1), and deficiency of this enzyme disrupts signaling and endocytosis involving the Golgi apparatus and organelles, resulting in developmental and functional abnormalities of the eyes, brain, kidneys, and other organs.
• Summary of pathophysiology
  • OCRL1 enzyme deficiency → abnormalities in cellular signaling, membrane trafficking, and endocytosis → impaired development and function of the lens, renal proximal tubules, and central nervous system.
• Main symptoms (summary)
  • Ophthalmologic: Congenital cataracts (in almost all patients), glaucoma (about 50%), corneal degeneration and scarring, strabismus, nystagmus, and others.
  • Central nervous system: Neonatal hypotonia, delayed motor development (many patients acquire walking during infancy to childhood), intellectual disability (varying from mild to severe), seizures (about 50%), and behavioral characteristics (including sociability and a preference for music, along with attention difficulties and compulsive behavior).
  • Renal: Fanconi-like findings due to proximal tubule damage — renal tubular acidosis, tubular proteinuria, aminoaciduria, nephrocalcinosis, rickets, and progressive decline in kidney function (chronic kidney failure).
  • Other: Growth delay (short stature), craniosynostosis, cryptorchidism, fine hair and pale skin, and a risk of weakness and malnutrition after obesity during infancy and early childhood.
• Diagnosis
  • Suspected based on clinical findings (cataracts, decreased muscle tone, proximal tubule abnormalities, etc.) → confirmed by molecular genetic testing of the OCRL gene. Enzyme activity testing in cultured tissue (skin) may provide supportive diagnostic information. Blood and urine tests to assess electrolytes and acid-base status, proteinuria and aminoaciduria, kidney imaging (such as ultrasound for nephrocalcinosis), and neurologic and ophthalmologic evaluations are needed.
• Prevalence
  • This is a very rare disease, and no differences between ethnic groups have been reported. Its incidence is not precisely known.

Treatment

• There is no curative treatment, and multidisciplinary conservative (symptomatic) management is the standard.
• Ophthalmology
  • Early surgery for congenital cataracts may be considered to preserve vision (optical correction and low-vision rehabilitation are needed after surgery). Medication and surgical treatment for glaucoma.
  • Regular ophthalmologic follow-up examinations are essential.
• Renal management (renal tubular abnormalities)
  • Correction of metabolic acidosis: Oral bicarbonate administration.
  • Electrolyte and phosphate supplementation, and active vitamin D (or alfacalcidol/calcitriol) for the treatment and prevention of rickets.
  • Fluid and electrolyte management, monitoring of kidney function (glomerular filtration rate and creatinine), and management of nephrocalcinosis.
  • If kidney function declines progressively, dialysis and kidney transplantation may be considered by a nephrologist.
• Neurologic and developmental care
  • Seizures are controlled with standard antiseizure medications (individually tailored). Physical therapy, occupational therapy, speech therapy, and special education support functional improvement.
  • If behavioral or psychiatric problems are present, medication and symptom management may be combined with behavioral therapy.
• Nutrition and growth
  • Monitor nutritional status and provide nutritional supplementation (such as calories and protein) when needed; supplement calcium, phosphate, and vitamin D to support skeletal health.
• Prevention and other care
  • Infection prevention (vaccination is recommended) and prompt treatment of respiratory infections such as pneumonia.
  • Avoid nephrotoxic medications (for example, some antibiotics and nonsteroidal anti-inflammatory drugs).
  • Genetic counseling and molecular genetic testing are recommended for family members who may be carriers.
• Treatment of complications
  • Specialty-specific treatment for complications such as chronic kidney failure, respiratory infections, fractures, and severe vision loss.

Checklist Before an Outpatient Visit (Including Example Questions)

• Items to prepare (recommended to bring)
  • A list of currently used medications and supplements (including doses and administration times).
  • Results of previous tests (genetic tests, blood and urine tests, kidney, ophthalmologic, and brain imaging, and written findings).
  • Records of recent weight and height (growth chart), urine volume and urination patterns, and changes in dietary and fluid intake.
  • Records of seizures (frequency, characteristics, triggers, and any available videos or EEG data).
  • Surgical and hospitalization history (including ophthalmologic surgery) and anesthesia history.
  • Photos (such as the condition of the eyes or skin) or notes on changes in symptoms observed at home.
• Symptoms that should be reported to the treating physician in advance at an outpatient visit (report immediately)
  • Sudden worsening of vision, new or uncontrolled seizures, dehydration, vomiting, markedly reduced urine output, lethargy, or difficulty breathing.
• Example questions to prepare before the consultation (for patients and caregivers)
  • Have there been any changes in kidney function (creatinine and eGFR) on recent tests?
  • What are the purposes and side effects of the medications currently being used?
  • What tests are scheduled next, and how often should they be performed?

Examples of General Questions to Ask the Doctor

• What is the expected overall prognosis of this disease (short-term and long-term)? What are the main causes of death?
• What are the main side effects of the currently prescribed medications, and which tests (such as blood tests) need to be monitored?
• What precautions should be taken in daily life (exercise, diet, school life, infection prevention, etc.)?
• When should genetic testing and prenatal testing be recommended for family members (especially female carriers), and which tests should be performed?

Examples of Disease-Specific Questions

• Regarding genetic testing
  • "How should the OCRL variant identified in me (or my son) be interpreted—is it a pathogenic variant (disease-causing)? Should genetic testing or carrier testing be recommended for family members (my mother or female relatives)?"
• Regarding kidney management
  • "Based on my current (or recent) blood and urine test results, which medications, dietary measures, and tests (such as a 24-hour urine test or kidney ultrasound), and what follow-up schedule, are recommended to preserve kidney function?"
• Ophthalmology (optional)
  • "If cataract surgery is needed, what is the optimal timing and what visual prognosis can be expected after surgery? What precautions are needed before and after surgery?"

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If needed, sharing recent test results (the genetic test report and kidney and ophthalmologic test values) can help with more specific preparation for the consultation and a tailored list of questions.